Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:73][CH:74]([SH:76])[CH3:75].C(N(C(C)C)C(C)C)C.C(Cl)[Cl:87]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[ClH:87].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([S:76][CH:74]([CH3:75])[CH3:73])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:18]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Reactant: CC(C)S
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Sc1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](N)C1
Product: Cl
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.314 mmol; Example 29, Step B), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (18.1 mg, 0.0314 mmol), Pd2 dba3 (14.4 mg, 0.0157 mmol), propane-2-thiol (71.6 mg, 0.941 mmol), and N-ethyl-N-isopropylpropan-2-amine (109 μL, 0.627 mmol) were placed in dioxane (1 mL) and heated to 150° C. under microwave irradiation for 2 hours. DCM and water were then added to the reaction mixture. The layers were separated, and the organic was washed with 1M NaOH. The organic layer was dried, filtered, and concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95% CH3CN/water). The product was then dissolved in TFA (2 mL) and stirred for 15 minutes. The reaction was concentrated, and the resulting residue was dissolved in 10% MeOH in DCM and then added dropwise to a stirred solution of 2M HCl in ether. The reaction was concentrated to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-(isopropylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (72 mg, 51% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.21 (s, 1H), 7.27 (s, 1H), 3.91 (d, 1H), 3.65 (m, 1H), 3.52 (d, 1H), 3.27-3.09 (m, 3H), 2.15 (m, 1H), 1.81-1.70 (m, 3H), 1.57 (m, 1H), 1.08 (dd, 6H), 0.94-0.80 (m, 4H). LCMS (APCI+) m/z 374.1 (M+H)+, Retention time=2.38 minutes (Method 3).
Reaction SMILES: N#N.[C:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])[CH3:4].[CH2:12]1CCN2[C:15](=[N:16]CCC2)[CH2:14][CH2:13]1.BrCCCC#N>CCOCC>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][N:6]([C:3](=[O:5])[CH3:4])[CH2:7][CH2:8]1
Reactant: CC(=O)N1CCNCC1
Reactant: C1CCC2=NCCCN2CC1
Agent: N#CCCCBr
Agent: N#N
Solvent: CCOCC
Product: CC(=O)N1CCN(CCCCN)CC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-acetylpiperazine (256 mg, 2.00 mmol) and DBU (0.30 mL, 2.00 mmol) in dry Et2O (2 mL) was added 4-bromobutyronitrile (0.21 mL, 2.00 mmol) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. The mixture was filtered and concentrated under reduced pressure. A 0.087 mol/L solution of the crude nitrile in EtOH (10 mL) was hydrogenated at 50° C. using the H-Cube® (1 mL/min) with a Raney Nickel cartridge (30 mm) under 50 bar until completion of the reaction. The solution was then concentrated under reduced pressure to give crude 1-(4-(4-aminobutyl)piperazin-1-yl)ethanone as a colorless oil. GC-MS-conditions 01: tR=2.94 min; [M+H]+=200.40.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:7]1[CH:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1cccc(NCCBr)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NCCNc2cccc(Cl)c2)C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 74.2 %

Procedure:
A mixture of 3-chloroaniline (50 g, 0.39 mol) and 1,2-dibromoethane (73 g, 0.39 mol) in MeCN (500 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated on rotavap and subjected to silica flash column chromatography using 0 to 30% EtOAc in PE to isolate N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 10%) as a yellow solid. To a solution of N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 38.46 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.74 g, 38.46 mmol) in THF (100 mL) was added DIEA (14.88 g, 115.38 mmol). The resulting mixture was stirred at 70° C. for 2 days. It was partitioned in EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous was extracted with EtOAC (50 mL×3). The combined organic layer was washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 5% MeOH in DCM to isolated (R)-tert-butyl 3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398) (10.1 g, 74.4%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2.N1C=CC=CC=1.CS([Cl:30])(=O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:30][CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:16]=[CH:17][CH:18]=[N:19][C:5]=3[N:4]([CH2:3][O:2][CH3:1])[C:9]=2[CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCN1c2cc(CO)ccc2Sc2nccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCN1c2cc(CCl)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a solution of 19 g of 10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-methanol and 13.9 ml of pyridine in N,N-dimethylformamide (150 ml) was added dropwise under a nitrogen atmosphere 13.3 ml of methanesulfonyl chloride at 0° C. Then the reaction mixture was stirred at room temperature for 1 hour and then poured into a pre-cooled aqueous solution of methylene chloride/sodium hydrogen carbonate. Then it was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with methylene chloride) to thereby give 13.6 g of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[S:25].NCCC(O)=O.O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:23]2[N:19]([CH3:18])[C:20](=[S:25])[NH:21][C:22]2=[O:24])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN1CC(=O)NC1=S
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=S)NC(=O)C1=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 5 h
Yield: 62.4 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (19.0 g, 81 mmols), 1-methyl-2-thioxo-4-imidazolidinone (10.6 g, 81 mmols) and beta-alanine (4.7 g, 53 mmols) in acetic acid (150 ml) is stirred under an inert atmosphere and heated to reflux. After 5 hours the mixture is allowed to cool, and is stirred into water (1.5 L). After an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1-methyl-2-thioxo-4-imidazolidinone (17.5 g), mp 242°-244° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1.C(O)(=O)C.CO>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1
Reactant: Clc1nc2ccnn2c(Cl)c1-c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1nc2ccnn2cc1-c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 1 g 5,7-dichloro-6-phenylpyrazolo[1,5-a]pyrimidine, 0.5 mL glacial acetic acid, 1 mL methanol, 6 mL THF and 730 mg of Zn/Cu pair were stirred for 3 h at 50° C. The mixture was filtered through celite, evaporated to dryness and the residue was purified on silica gel (hexanes/ethyl acetate) to yield 550 mg of a 1:1 mixture of the desired product and the starting material, which was used without further purification.
Reaction SMILES: C1(S(N2C3=NC=C([N+]([O-])=O)C(Cl)=C3C=C2)(=O)=[O:8])C=CC=CC=1.[CH2:23]([N:30]1CC[CH:33]([NH2:36])[C:32]([F:38])(F)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N([CH:45]([CH3:47])C)CC)(C)C>CC(O)C>[F:38][C:32]1[CH:33]=[N:36][CH:45]=[CH:47][C:31]=1[NH:30][C:23](=[O:8])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1(F)F
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccncc1F)c1ccccc1
Temperature: 80 °C
Yield: 240.1 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (4.6 g, 14 mmol), 1-benzyl-3,3-difluoropiperidin-4-amine (prepared according to EP2123651 A1, 3.08 g, 13.6 mmol), diisopropylethylamine (6 mL, 34 mmol) in propan-2-ol (100 mL) was heated at 80° C. for 12 hours. The mixture was concentrated, suspended in potassium bisulfate solution (1N, 100 mL), and filtered to yield 7.06 g of a yellow solid (LCMS (Method F, ESI): RT=1.28 min, m+H=528.3). The solid was suspended in ethanol (90 mL) and water (30 mL), iron powder (2.3 g, 41 mmol) and ammonium chloride (3.6 g, 68 mmol) was added, and the mixture was refluxed for 4 hours. The mixture was filtered through CELITE®, thoroughly washing the filter cake with ethanol and ethyl acetate. The filtrate and washings were combined and concentrated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer dried with sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 0 to 50% (20% methanol in ethyl acetate) in heptanes) affording 4.6 g (68%) of 1-Benzenesulfonyl-N*4*-(1-benzyl-3,3-difluoro-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine as a purple solid (LCMS (Method F, ESI): RT=0.83 min, m+H=490.3). 1H NMR (400 MHz, DMSO) δ 8.02 (d, J=7.9 Hz, 2H), 7.72-7.62 (m, 2H), 7.57 (t, J=7.7 Hz, 2H), 7.50 (d, J=4.2 Hz, 1H), 7.40-7.22 (m, 5H), 6.82 (d, J=4.2 Hz, 1H), 5.17 (d, J=9.9 Hz, 1H), 4.46 (s, 2H), 4.27-4.08 (m, J=16.0, 13.3, 8.1 Hz, 1H), 3.69-3.52 (m, 2H), 3.04 (dd, J=16.5, 10.6 Hz, 1H), 2.80 (d, J=11.5 Hz, 1H), 2.60-2.42 (m, J=11.9 Hz, 1H), 2.31 (t, J=11.0 Hz, 1H), 1.91 (d, J=13.0 Hz, 1H), 1.85-1.69 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:25](=[O:26])[CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: Cc1noc(-c2sc(NC(=O)Cc3cccs3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and thiophen-2-yl-acetyl chloride.
Reaction SMILES: C[O-].[Na+].[P:4]([O-:11])([O:8][CH2:9]C)[O:5][CH2:6]C.[CH:12]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])=O.CS(O)(=O)=O>CO>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]([P:4](=[O:11])([O:8][CH3:9])[O:5][CH3:6])[O:18]1
Reactant: CCOP([O-])OCC
Reactant: O=Cc1ccccc1C(=O)O
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of sodium methoxide (5.4 M, 4.8 mL) in MeOH (20 mL) was added diethyl phosphite (3.31 g, 24 mmol) at 0° C. followed by addition of 2-formylbenzoic acid (3.0 g, 20 mmol) portion-wise over a period of 20 min. The resulting mixture was warmed up to rt and continued to stir for 2 h. Methanesulphonic acid (2.69 g, 28 mmol, 1.4 equiv.) was added to the above mixture over a period of 30 min. The reaction mixture was stirred for 30 min and concentrated to remove most of the MeOH. The residue was partitioned between DCM (100 mL) and water (50 mL). The aqueous layer was extracted DCM twice. The combined organic layer was dried over Na2SO4 and concentrated to give dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (4.6 g, 90%). LRMS (M+H+) m/z 257.1.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCCCC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: CCCCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and valeryl chloride. m.p.: 159-160° C. 1H-NMR (CDCl3) δ: 9.94 (1H, br s), 8.28 (1H, d, J=9.2 Hz), 8.19 (1H, br s), 7.77 (1H, t, J=1.8 Hz), 7.70-7.58 (2H, m), 7.51 (1H, t, J=7.7 Hz), 7.31 (1H, d, J=1.8 Hz), 7.11 (1H, dd, J=1.8, 8.8 Hz), 2.49 (2H, t, J=7.3 Hz), 1.81-1.70 (2H, m), 1.51-1.37 (2H, m), 0.97 (3H, t, J=7.3 Hz)
Reaction SMILES: [Cl-:1].C([NH:5][C:6]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N+:12]1[CH:16]=[CH:15][N:14]([CH3:17])[CH:13]=1)(=O)C>C(O)C>[Cl-:1].[ClH:1].[ClH:1].[NH2:5][C:6]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N+:12]1[CH:16]=[CH:15][N:14]([CH3:17])[CH:13]=1
Reactant: CC(=O)Nc1ccc(N)cc1OCCC[n+]1ccn(C)c1
Agent: [Cl-]
Solvent: CCO
Product: Cl
Product: Cn1cc[n+](CCCOc2cc(N)ccc2N)c1

Procedure:
The 1-[3-(2-acetylamino-5-aminophenoxy)propyl]-3-methyl-3H-imidazol-1-ium chloride obtained in the above step (19.0 g) was dissolved, at room temperature and with stirring, in 90 ml of approximately 5N absolute hydrochloric ethanol.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].C([Li])CCC.Cl.CC([O:25][CH3:26])(C)C.C1C[O:30]CC1>>[OH:4][C:5]1[C:6]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:8]=[CH:9][C:10]=1[C:26]([OH:25])=[O:30]
Reactant: COC(C)(C)C
Reactant: C1CCOC1
Reactant: COCOc1ccccc1C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Product: O=C(O)c1cccc(C(F)(F)F)c1O
Temperature: -20 °C
Reaction time: 1.17 h
Yield: 99 %

Procedure:
A solution of Example 42A (14.1 g, 68.4 mmol) in THF (68 mL) was cooled to −20° C. and n-butyllithium (30.1 mL of a 2.5 M solution in hexanes, 75.0 mmol) was added slowly, keeping the temperature at 0° C. After 70 min at −5 to 5° C., the reaction mixture was cooled to −20° C. and CO2 gas was bubbled through the brown slurry, keeping the temperature ≦−10° C. The reaction went from a brown slurry to a dark purple solution to a yellow solution. After 10 min, the reaction mixture was cooled further to −20° C. and treated with 2N HCl (68 mL, 140 mmol). To facilitate the reaction mixture, additional concentrated HCl (17 mL, total 5 equiv of 4M HCl) was added. After 30 min, MTBE (70 mL) was added, and the organic portion was extracted with 2N NaOH (70 mL) and water (70 mL). The aqueous layer was acidified with 2N HCl (98 mL) and extracted with dichloromethane (2×140 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (14.8 g, 71.8 mmol, 99%) as a yellow solid which was used without further purification. MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>O>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(O)c1
Solvent: O
Product: CC(=O)Nc1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Acetic anhydride (22.5 g; 220 mmol) was slowly added to a suspension of 24.0 g (220 mmol) of m-aminophenol in 60 g of crushed ice and 60 ml of cold water. The reaction mixture was vigorously stirred for 30 minutes. The white precititate was filtered, washed with cold water, and air-dried to give 30.5 g (92% yield) of pure 3-acetamidophenol.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To an ice cold solution of ethyl isonipecotate (60 g, 0.382 mol) and triethylamine (38.65 g, 0.382 mol) in tetrahydrofuran (360 ml) was added dropwise benzoyl chloride (53.7 g, 0.382 mol) over a period of about 2 hours under nitrogen atmosphere. The reaction mixture was stirred for about 2 hours at the same temperature, and was filtered. The filtrate was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. Crystallization from isopropyl alcohol gave the titled compound (90.9 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[C:4]([Cl:18])[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.[F-].[Cs+]>O1CCOCC1.O>[Cl:18][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[N:25][CH:26]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:22]=2)[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=1
Reactant: Fc1ccc(CNc2cc(Cl)nc(Cl)n2)c(F)c1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(CNc2cc(Cl)nc(-c3cncc(C(F)(F)F)c3)n2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of (2,6-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-benzyl)-amine (1 g, 0.0034 mol) and 5-trifluoromethylpyridine-3-boronic acid (0.726 g, 0.0038 mol) were taken in dioxane:water (20:5) ml and to this CsF (2.1 g, 0.0138 mol) was added and degassed. Then bis-triphenylphosphine-palladium(II) chloride (0.24 g, 0.00034 mol) was added and degassed. The mixture was stirred at 60° C. for 12 hrs. The reaction was cooled to room temperature diluted with water (50 ml) and ethyl acetate (100 ml). After standard work-up, the residue was purified by column chromatography to get compound as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([OH:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][N:28]1[C:32](=[O:33])[C:31]2[C:34]([CH:40]([CH3:42])[CH3:41])=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=2[S:29]1(=[O:44])=[O:43].O>CO.CN(C=O)C>[CH:40]([C:34]1[C:31]2[C:32](=[O:33])[N:28]([CH2:27][O:15][C:14]3[N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[N:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=3)[S:29](=[O:44])(=[O:43])[C:30]=2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=1)([CH3:42])[CH3:41]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
A mixture of 1-(4-nitrophenyl)-3-trifluoromethyl-5-hydroxypyrazole (450 mg; 1.65 mmol) and Cs2CO3 (269 mg; 0.825 mmol) in methanol (9 ml) was stirred at 20° C. for 4 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo overnight. To a solution of the above residue in 7 ml of DMF was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (479 mg, 1.37 mmol) and the resulting mixture was stirred at room temperature (20° C.) for 3 hours and then poured into water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 18-33% ethyl acetate in hexane) and recrystallized from methylene chloride/hexane to afford 350 mg (47%) of 4-isopropyl-6-methoxy-2-[1-(4-nitrophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-NO2 --Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 185°-187° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].O.[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccccc1C1=CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a mixture of 1-chloro-2-nitrobenzene (0.5 g, 3.2 mmol) and sodium carbonate (0.34 g, 3.2 mmol) in a 100 mL roundbottom flask equipped with a magnetic stir bar and nitrogen inlet were added water (3.2 mL), dioxane (13 mL) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 mL, 3.8 mmol). The reaction flask was evacuated and purged with nitrogen (2×) prior to the addition of bis(triphenylphosphine)palladium(II) chloride (0.18 g, 0.25 mmol), and then evacuated and purged (3×) following the addition of the catalyst. The reaction was heated to 80° C. and stirred overnight. The reaction was cooled and filtered through a pad of Celite® which was subsequently washed with water and ethyl acetate. The phases were separated and the organic phase was dried by passing it through a phase separator cartridge and concentrated. The residue was purified by flash column chromatography providing the title compound (0.56 g, 3.0 mmol, 93% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.78-7.71 (m, 1H), 7.54-7.47 (m, 1H), 7.40-7.32 (m, 2H), 5.86-5.82 (m, 1H), 2.63-2.55 (m, 2H), 2.55-2.47 (m, 2H), 2.09-1.98 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 148.77, 139.96, 133.58, 132.08, 130.87, 130.52, 127.55, 123.70, 35.31, 33.49, 24.05; ESIMS m/z 190 ([M+H]+).